The offspring of obese mothers consuming a high-fat diet during pregnancy are at a higher risk than the children of thin mothers for lifelong obesity and related metabolic disorders. The molecular and cellular basis for these differences are clarified in a new study published in the Jan. 23 issue of Cell by researchers at Yale School of Medicine and the University of Cologne.

Conducted in mice, the study showed that the offspring of mothers who consumed a high-fat diet during lactation had abnormalneuronal circuits in the hypothalamus -- a key brain region that regulates metabolism.

"Our study suggests that expecting mothers can have major impact on the long-term metabolic health of their children by properly controlling nutrition during this critical developmental period of the offspring," said the study's co-lead author Tamas Horvath , the Jean and David W. Wallace Professor of Biomedical Research and chair of comparative medicine at Yale School of Medicine.

Horvath and his collaborators at the Max Planck Institute for Neurological Research and at the University of Cologne developed a mouse model of metabolic programming. They found that mouse mothers fed a high-fat diet during breastfeeding had offspring with abnormal neuronal connections in the hypothalamus, as well as altered insulin signaling in this brain circuit. As a result, the offspring remained overweight and had abnormalities in glucose metabolism throughout life.

Horvath and his colleagues said the study helps identify the key point in pregnancy when maternal nutrition has the most impact on an offspring's metabolic health.

Because of developmental differences between species -- neural circuits in the hypothalamus continue to develop after birth in mice, but are fully developed before birth in humans -- the findings suggest that the third trimester of pregnancy in humans is the most critical period. That's when a mother's diet will most likely have long-lasting effects on her offspring's health, according to the researchers.

"Mothers can control or even reverse their offspring's predisposition to obesity and resulting diseases by altering their food intake," said Horvath. "Because gestational diabetes frequently manifests during the third trimester, the results could inform more intense screening of mothers for alterations in glucose metabolism."

The study was funded in part by the National Institutes of Health NIH (DP1 DK006850, R01AG040236, and P01NS062686), the American Diabetes Association, the Helmholtz Society (ICEMED), and The Klarman Foundation.